Method of making 21-fdelta1,4 pregnadiene compounds



United States Patent METHOD OF MAKING ZI-FA PREGNADIENE COMPOUNDS Josef Fried and Josef E. Herz,.New Brunswick, N.J., as-

signors to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Application July 18, 1956 Serial No. 598,539

4 Claims. (Cl. 260397.45)

This invention relates to the synthesis of steroids and has for its objects the provision of (I) an advantageous process of preparing the new steroids: 21-fiuoro-A pregnadiene-l1/3,l7a-diol-3,20-dione and 21-fiuoro-A pregnadiene-l7a-ol-3,l1,20-trione; and (II) these new steroids, which are useful in themselves as physiologically active steroids.

The process of this invention essentially comprises interacting a 21-alkanesulf0nic acid ester of A -pregnadiene-l1B,l7a,21-triol-3,20-dione or A -pregnadiene- 17a,2l-diol-3,l1,20-trione or the corresponding 21-chloro, bromo or iodo derivatives (e.g., 21-chloro-A -pregnadiene-ll,B,l7a-diol-3,20-dione) with potassium fluoride to form the corresponding 21-fiuoro derivatives, and, if an ll-keto final product is desired and an 11 ,B-hydroxy steroid is employed as the initial reactant, oxidizing the resultant llfi-hydroxy steroid to its ll-keto derivative.

Suitable starting materials utilizable in the process of this invention include the 21-alkanesulfonic acid esters (particularly the lower alkanesulfonic acid esters, as exemplified by the methanesulfonic acid ester) of A pregnadiene-llfi,17a,21-triol-3,20-dione and A -pregnadiene-17a,21-diol-3,l1,20-trione; 2l-chloro A pregnadiene-l 1 13,17 a-diol-3,20-dione; 21-chloro-A -pregnadienel7a-ol-3,ll,20-trione; 21-bromo A pregnadiene 110, 17a-diol-3,20-dione; 2l-bromo-A -pregnadiene 17a ol- 3,11,20-trione; 21-iodo-A pregnadiene 11 ,6,17u diol- 3,20-dione; and 2l-iodo-A -pregnadiene-l7a-ol-3,11,20- trione. In accordance with the process of this invention, one of these starting materials is interacted with potassium fluoride. This reaction is preferably conducted in an organic solvent of high dielectric constant, such as dimethylformamide, dimethylsulfoxide, and diethylene glycol, optimally at an elevated temperature, such as one in the range of about 100 C. to about 130 C.

If an ll 8-hydroxy steroid is employed as the starting material and an ll-keto final product is desired, the resulting 2l-fluoro-11B-hydroxy steroid can then be oxidized in the usual manner as by treating with a hexavalent chromium compound (e.g., chromic acid) in an acidic medium (e.g., glacial acetic acid) to yield the corresponding ll-keto derivative.

The 21-fluoro steroids of the n -pregnadiene series of this invention are physiologically active steroids which possess glucocorticoid activity. Thus, these new steroids of this invention can be administered instead of, and in the same manner as, cortisone or hydrocortisone in the treatment of rheumatoid arthritis and/ or dermatomyositis. The dosage for such administration is, of course, dependout on the relative activity of the compound.

lCc

2 The following examples are illustrative-of the invention (all temperatures being in centigrade) EXAMPLE 1 21-flu0r0-A -pregnadiene-J1,B,17a-diol-3,20-di0ne and A -pregnadiene-17m21-0xid0-1 1fi-0l-3,20-di0ne (a) PREPARATION OF A -PREGNADIENE-11B,17a,21- TRIOL-3,20-DIONE 21-MESYLATE' max.

Analysis.Calcd. for C22H30O7SI C, 60.26; H, 6.90.

Found: C, 60.21; H, 6.89.

(b) REACTION OF A -PREGNADIENE-11fi17a,21-TRIOL- 3,20-DIONE 21-MESYLATE WITH POTASSIUM FLUO- RIDE A solution of 1 g. of A -pregnadiene-11 8,17a,21-

triol-3,20-dione 21-mesylate and 1.0 g. of anhydrous potassium fluoride in 50 ml. of dimethylsulfoxide is heated at 110 with stirring for 24 hours. After cooling, the mixture is diluted with ice water and the resulting precipitate (about 570 mg.) filtered OE and washed with water. The precipitate is separated by extraction with hot chloroform into the chloroform-insoluble 21-fluoride and the chloroform-soluble 17a,21-epoxide. The 21- fluoride-A -pregnadiene-l1,3,17a-diol-3, 20-dione, on recrystallization from acetone, has the following properties:

M.P. about 257-262"; [(21 +86 (c., 0.31 in dioxane);

Age, 243 m ($15,100 mi 2.90, 3.00, 5.74., 0.04

AL}; 243 m (e=l5,400); 2.99, 5.53, 6.03, 6.20

Analysis.-Calcd. for C H O (342.42): C, 73.66; H, 7.66. Found: C, 73.58; H, 7.48.

EXAMPLE 2 21-flu0r0-A -pregnadiene-l 7a-0l-3,11,20-tri0ne To a solution of mg. of 21-fiuoro-A -pregnadiene 11/3,l7a-diol-3,20-dione in 5 ml. of glacial acetic acid is added a solution of 40 mg. of chromic acid in 4 ml. of acetic acid. A half-hour later, 0.5 ml. of methanol is added, and the resulting mixture is concentrated in vacuo. The residue is taken up in water, and extracted with ethyl acetate. After drying over sodium sulfate and evaporation of the solvent in vacuo, the residue is crystallized from 95% ethanol to give pure 21-fluoro-A -pregnadiene-17a-ol-3,l1,20-trione.

The invention may be otherwise variously embodied within the scope of the appended claims.

We claim:

1. A process for preparing a steroid selected from the group consisting of 21-fiuoro-A -pregnadiene-l1 3, l7oz-diOl-3,20-di0l16 and 21-fluoro-A -pregnadiene-17aol-3,11,20-trione, which comprises interacting a steroid selected from the group consisting of the 2l-(lower alkane) sulfonic acid esters of A -pregnadiene-l1;8,17a, 2l-triol-3-20-dione and A pegnadiene 17oc,21 diol- 3,11,20-trione with potassium fluoride under substantially anhydrous conditions and recovering the resulting 21- fluoro steroid. v

2. A process for preparing a steroid selected from the group consisting of 21-fluoro-A -pregnadiene-115,170;-

diol-3,20-dione and 21-fluoro-A pregnadiene 17u-Olg0 3,11,20-tn'one, which comprises interacting a steroid selected from the group consisting of the 21-(lower alkane) sulfonic acid esters of A1,4-pregnadiene-ll}3,17a, 21-triol-3,2O dione and A pregnadiene 1711,21 diol- 3,11,20-trione with potassium fluoride under substantially anhydrous conditions at an elevated temperature in an organic solvent of high dielectric constant, and recovering the resulting 21-fluoro steroid.

3. The process of claim 2 wherein the steroid reactant is a ZI-methanesulfonic acid ester.

4. A process for preparing 21-fiuoro-A -pregnadiene- 11,3,17u-diol-3,20-dione which comprises interacting A regnadiene-I1fi,17a,21-triol-3,20-dione 2l-mesylate with potassium fluoride under substantially anhydrous conditions at an elevated temperature in an organic solvent of high dielectric constant, and recovering the resulting 2l-fiuoro steroid.

No references cited. 

1. A PROCESS FOR PREPARING A STEROID SELECTED FROM THE GROUP CONSISTING OF 21-FLUORO-$1,4-PREGNADIENE-11B, 17A-DIOL-3,20-DIONE AND 21-FLUORO-$1,4-PREGNADIENE-17AOL-3,11,20-TRIONE, WHICH COMPRISES INTERACTING A STEROID SELECTED FROM THE GROUP CONSISTING OF THE 21-(LOWER ALKANE) SULFONIC ACID ESTERS OF $1,4-PREGNADIENE-11B,17A, 21-TRIOL-3-20-DIONE AND $1,4 - PEGNADIENE - 17A,21 - DIOL3,11,20-TRIONE WITH POTASSIUM FLUORIDE UNDER SUBSTANTIALLY ANHYDROUS CONDITIONS AND RECOVERING THE RESULTING 21FLUORO STEROID. 